1. Field of the Disclosure
The present disclosure relates generally to compounds useful for the inhibition of human secreted phospholipase A2. More specifically, the disclosure relates to the use of certain amides derived from non-natural amino acids as inhibitors.
2. Background Information
The phospholipase A2 (PLA2) superfamily of enzymes consists of a broad range of enzymes defined by their ability to catalyze the hydrolysis of the ester bond at the sn-2 position of phospholipids, yielding free fatty acids, including arachidonic acid, and lysophospholipids. The characterization and classification of PLA2 enzymes as well as their role in pathophysiological conditions are known. PLA2 enzymes have been systematically classified into 15 groups and subgroups on the basis of their nucleotide and amino acid sequence. According to a broader classification the PLA2 classes have been historically classified into three types: secretory (sPLA2), cytosolic Ca2+-dependent (cPLA2) and cytosolic Ca2+-independent (iPLA2).
The Group IVA cPLA2 (GIVA cPLA2) is a particularly attractive target for drug development, since it is the rate-limiting provider of arachidonic acid and lysophospholipids that can be converted into prostaglandins, leukotrienes and PAF, respectively. Various studies on gene-targeted mice that lack GIVA cPLA2 showed that prostaglandins and leukotriene production was reduced by approximately 90%, confirming the primacy of GIVA cPLA2 in lipid mediator production. Recently, it was demonstrated that GIVA cPLA2 plays an important role in the pathogenesis of autoimmune encephalomyelitis (which models multiple sclerosis), and that cytosolic phospholipase A2-deficient mice are resistant to experimental autoimmune encephalomyelitis.
The role of the other intracellular PLA2, calcium-independent PLA2 (GVIA iPLA2), in the inflammatory process is still unclear, and it has not been a target for the development of novel medicines. This enzyme appears to be the primary PLA2 for basal metabolic functions within the cell.
It has been shown that in macrophages and other cells, GIVA cPLA2 and secretory phospholipase A2 work together to release arachidonic acid. Several experiments suggest that GV sPLA2 has a role in amplifying the action of GIVA cPLA2 in supplying arachidonic acid for eicosanoid production. In addition, GV sPLA2 has functions independent of its ability to provide arachidonic acid that include regulation of phagocytosis and foam cell formation, suggesting a potential role in inflammatory processes such as atherosclerosis.
Amide phospholipids analogues of substrates can inhibit the activity of secreted PLA2 (e.g., compound 1 shown in FIG. 1). Compound 2 (also shown in FIG. 1) is also as a potent inhibitor of sPLA2. Non-phospholipid amide compounds based on non-natural amino acids, such as compounds 3 and 4 (FIG. 1) can inhibit the activity of pancreatic and non-pancreatic GI and GII sPLA2, and compound 4 has been reported to protect rat small intestine from I/R injury and TNBS-induced colitis.
The selective inhibition of the various PLA2 classes is very important to understand their specific roles in cells and in vivo and develop therapeutic strategies accordingly. Accordingly, a variety of amides based on non-natural amino acids have been synthesized and their specific inhibitory activity on three human PLA2 classes: GIVA cPLA2, GVIA iPLA2, and GV sPLA2 demonstrated as described below in the present application.